Background. Human genetic polymorphisms in metabolic activation and detoxification pathways are a major source of inter-individual variation in susceptibility to environmentally induced disease. The group has developed genotyping assays for the at-risk variants of enzymes that protect against carcinogens in cigarette smoke, diet, industrial processes and environmental pollution. Population studies indicate that for these candidate susceptibility genes, the frequency of the at-risk genotypes for glutathione transferase M1 (GSTM1), theta 1 (GSTT1), Pi (GSTP1), N-acetyltransferase (NAT1 and NAT2), XRCC1, XPD, P53 pathway, and NRF2 pathway vary significantly between ethnic groups. Some differences in cancer incidence among groups may be due to genetic differences as well as exposure differences. Mission: Our long-term goal is to understanding how genes, the epigenome and the environment interact to influence risk of environmentally induced disease. To this end we are engaged in Environmental Epigenomics. This encompasses: 1) identification of candidate environmental response genes, 2) discovery and functional characterization of genetic, epigenetic and phenotypic variation in these genes, and; 3) the analysis in population studies of environmental disease susceptibility associated with functional polymorphisms, acquired susceptibility factors such as epigenetic changes and environmental exposures; and the interactions between these factors. Eventually we hope these genomic approaches may identify biomarkers of exposure and effect, that will be predictive of future risk, and potentially useful in precision medicine. A current primary focus is to look at methylation levels of CpG sites in the human genome in relationship to exposures. Methylation profiles in blood and other tissues have promise as exposure biomarkers, markers of early pathology or perhaps biomarkers of disease. This information will allow us to more carefully determine the bounds of human variability to guide risk assessment and may be useful in developing prevention strategies to reduce disease incidence. In the Genetic Susceptibility Project we take the candidate susceptibility factors from the laboratory genotype/phenotype studies and test them in population studies. We are collaborating with numerous NIH, and university-based epidemiology groups to design and carryout appropriate tests of these factors in population-based epidemiology studies. Progress/accomplishments: 1) The ability of p53 to regulate transcription is crucial for tumor suppression and implies that inherited polymorphisms in functional p53 binding sites could influence cancer. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants and expression quantitative trait loci (eQTLs) in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The p53 pathway cancer-associated polymorphisms have strikingly similar characteristics to well-studied p53 pathway mutations. Our results enable insights into p53-mediated tumor suppression in humans and into p53 pathway-based surveillance and treatment strategies Stracquadanio et al. We not working on p53 in FY18. 2) We are examining CpG methylation in cord blood in relation to maternal smoking and in blood of adult smokers. Epigenetic modifications due to in utero exposures may play a critical role in early programming for childhood and adult illness. Little is known regarding the epigenetic basis of atherosclerosis. Here we present the CD14+ blood monocyte transcriptome and epigenome signatures associated with human subclinical atherosclerosis. The transcriptome signatures included transcription coactivator, ARID5B (AT-rich interactive domain 5B), which is known to form a chromatin derepressor complex with a histone H3K9Me2-specific demethylase and promote adipogenesis and smooth muscle development. ARID5B CpG (cg25953130) methylation was inversely associated with both ARID5B expression and atherosclerosis, consistent with this CpG locus residing in an ARID5B enhancer region, based on chromatin-capture and histone marks data. Mediation analysis supports assumptions that ARID5B expression mediates effects of cg25953130 methylation and several cardiovascular disease risk factors on atherosclerotic burden. In lipopolysaccharide-stimulated human THP1-monocytes, ARID5B knockdown reduced expression of genes involved in atherosclerosis-related inflammatory and lipid metabolism pathways, and inhibited cell migration and phagocytosis. Together, these data suggest that ARID5B expression, possibly regulated by an epigenetically controlled enhancer, promotes atherosclerosis by dysregulating immunometabolism towards a chronic inflammatory phenotype (Liu et al, 2017)